# Identifying and Targeting 3D Regulatory Nodes that Maintain Glioblastoma Programs

> **NIH NS R01** · WEILL MEDICAL COLL OF CORNELL UNIV · 2026 · $675,615

## Abstract

PROJECT SUMMARY
Glioblastoma (GBM) is a highly aggressive and incurable brain tumor. The inter-patient and intra-tumoral
heterogeneity of GBM, resulting from genetic alterations and epigenetic plasticity, poses a major challenge in its
treatment. GBM IDH-wt tumors are composed by different proportions of transcriptionally defined cell states,
which although resemble neurodevelopmental cell types, are highly plastic and interconvertible -rather than
hierarchic- as we and others have shown. This suggests the presence of a core regulatory logic that enables
toggling among different transcriptional states, endowing GBM tumors with increased phenotypic plasticity and
fitness. Here, we aim to unravel core regulatory modules that are critical for GBM programs with a particular
focus on enhancers, which together with transcription factors govern cell-state specific programs. Enhancer
dysregulation by genetic variants and epigenetic mechanisms is increasingly appreciated as a key process in
oncogenic transformation and drug resistance. However, dissecting and modulating enhancer function remains
very challenging due to the large number of putative enhancers and the complex ways they control their target
genes in the context of the three-dimensional (3D) genome. By constructing 3D enhancer-promoter interaction
networks in four patient-derived glioma stem-like cells (GSCs) and normal neuronal stem cells -as controls- we
have identified a subset of GSC-specific hyperconnected enhancers, which we coin "3D regulatory hubs”. 3D
hubs harbor genes with robust and coordinated transcriptional levels that enrich for oncogenic pathways and are
associated with worse patient outcomes. Importantly, epigenetic perturbation of a highly-recurrent enhancer hub
in GSCs resulted in concordant donwregulation of multiple hub-connected genes, leading into significant shifts
in the transcriptional states and altered clonogenic and proliferation capacities. Building on this foundational
work, we prop

## Key facts

- **NIH application ID:** 11317181
- **Project number:** 5R01NS136475-03
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** Effie  Apostolou; Howard A. Fine; EKTA  KHURANA
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NS
- **Fiscal year:** 2026
- **Award amount:** $675,615
- **Award type:** 5
- **Project period:** 2024-05-01T00:00:00 → 2029-04-30T00:00:00

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11317181

## Citation

> US National Institutes of Health, RePORTER application 11317181, Identifying and Targeting 3D Regulatory Nodes that Maintain Glioblastoma Programs (5R01NS136475-03). Retrieved via AI Analytics 2026-07-04 from https://api.ai-analytics.org/grant/nih/11317181. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*